Journal of the National Cancer Institute Advance Access originally published online on April 28, 2009
JNCI Journal of the National Cancer Institute 2009 101(9):618-621; doi:10.1093/jnci/djp080
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© The Author 2009. Published by Oxford University Press.
EDITORIALS |
The Plight of the Potato: Is Dietary Acrylamide a Risk Factor for Human Cancer?
Affiliations of authors: Department of Epidemiology (LAM, H-OA), Harvard School of Public Health, Boston, MA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (H-OA), Channing Laboratory, Brighman and Women's Hospital, Harvard Medical School, Boston, MA (LAM)
Correspondence to: Lorelei A. Mucci, ScD, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, 9th floor, Boston, MA 02115 (e-mail: lmucci{at}hsph.harvard.edu).
Ensuring the safety of the food supply has been one of the major accomplishments of the public health system. Thus, in 2002, when the Swedish National Food Administration reported for the first time that acrylamide was detected in commonly consumed baked and fried foods, the report generated considerable public health alarm (1). The sense of alarm was based on acrylamide's classification by the International Agency for Research on Cancer as a class 2A "probable human carcinogen" (2) and the realization that acrylamide is ubiquitous in the human diet. It is found in the highest concentrations in French fries and potato chips, but it is also detected in diverse foods such as breads, cereals, cakes, and coffee and cocoa (3). Indeed, more than one-third of the calories we take in each day come from foods with detectable levels of acrylamide (4).
Given that the compound is found throughout the food supply, researchers and national food administrations wondered whether dietary acrylamide could be an important human cancer risk factor (5). The public concern was reflected in the substantial decreases in sales of potato chips in the months immediately following the discovery of acrylamide in foods (6).
Since the discovery of acrylamide in commonly consumed foods, researchers have identified the mechanism of acrylamide formation. Rather than being a food contaminant, acrylamide forms as a by-product of cooking specific foods at high temperatures through a Maillard reaction between amino acids, primarily asparagine, and reducing sugars such as fructose or glucose (7). Understanding the mechanism has led to considerable research efforts around strategies to reduce the amount of acrylamide that is created in foods, including altering levels of asparagine or sugars, or by reducing temperatures at which foods are cooked (8,9). These efforts are important if there is concern of a small excess risk even at the low levels of exposure that prevail in most human populations.
Still, the question of whether the amount of acrylamide in foods was sufficient to cause cancer in humans was a matter of considerable debate (10,11). The doses which animals were given are 1000–10 000 times higher than levels to which humans are exposed daily through dietary sources, which average 0.5–1.0 µg/kg body weight (12).
Over the 6 years following the initial Swedish report, a large number of epidemiological studies have examined dietary exposure to acrylamide in relation to risk of cancer at multiple sites (summarized in Table 1). The results of these studies, in combination with experimental and toxicological studies, are the primary evidence on the relation between acrylamide in the human diet and cancer risk.
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The findings from epidemiological studies have converged in indicating no positive association between total dietary acrylamide intake and risk of colorectal cancer (13,16,20–22), bladder cancer (13,14), esophageal cancer (16,22), and prostate cancer (16,24). Similarly, no associations have been reported with risk of oropharyngeal (16), laryngeal (16), pancreatic (22), and gastric (22) cancers, although the findings for these cancers were based on results from only one study.
For breast cancer, studies based on food frequency questionnaires (FFQs) have consistently reported no positive association between estimated dietary acrylamide intake and risk of pre- or postmenopausal breast cancer, or breast cancer defined by estrogen and progesterone receptor status (15,17–19). These findings appear in contrast with a biomarker study nested within a Danish cohort, in which higher levels of hemoglobin–acrylamide adducts were associated with an increased risk of estrogen receptor–positive tumors (26). However, the relevance of these findings to dietary exposure to acrylamide is unclear because the association was statistically significant among smokers only, who on average inhale five times more acrylamide than they consume in their diet (12).
For renal cell cancer and ovarian cancer, results from epidemiological studies are inconsistent. Two population-based case–control studies in Sweden found no association between dietary acrylamide and renal cell cancer risk, with relative risk estimates of 1.0–1.1 (13,25), but a case–cohort study nested within the Netherlands cohort reported a 60% increased risk (14). The same Dutch study found a positive association with increased intake of dietary acrylamide for ovarian cancer risk and also endometrial cancer risk among nonsmokers (17). In contrast, the prospective Swedish mammography study found no association between acrylamide intake and either ovarian or endometrial cancer (18,23). To address the positive findings for renal, ovarian, and endometrial cancers in the Netherlands cohort study, follow-up research should be undertaken in additional populations using dietary and biomarker assessments of acrylamide.
In this issue of the Journal, the investigators of the Netherlands cohort present data on the relation between dietary intake of acrylamide and risk of lung cancer. No epidemiological study of acrylamide and lung cancer has previously been reported, and we commend the researchers for expanding the state of knowledge around the possible carcinogenic effects of acrylamide. With a large number of case subjects, the authors report no evidence of a positive association between acrylamide intake from foods and lung cancer risk. Indeed, they found no overall association among men and unexpectedly found an inverse association between acrylamide intake and lung cancer risk among women. A critical question in interpreting the results is whether this finding reflects a causal association, that is, "that acrylamide might protect against lung cancer in women" as the authors state in the discussion—or is there an alternate explanation?
The Netherlands cohort study is well designed with careful follow-up and a validated FFQ (27). In this setting, the use of the case–cohort design is a valid and efficient approach. Rather than coding dietary information on the entire cohort, the case–cohort takes a random sample of the cohort at baseline to represent the exposure distribution of the underlying cohort. Given potentially different etiologies of cancer subtypes, it is an additional strength of the present analysis that the authors provide analyses for lung cancer histological subtypes, with sufficient numbers to assess associations with dietary acrylamide. The authors have adjusted for a number of lung cancer risk factors, including smoking exposure, for which there was a fine level of control.
There are limitations in epidemiological approaches that are particularly relevant for assessing acrylamide intake as a cancer risk factor. Hogervorst et al. presented a thoughtful discussion of the potential limitations of using the FFQ to estimate total exposure to dietary acrylamide. Studies comparing estimates based on the FFQ to biomarkers of acrylamide exposure suggest correlation coefficients on the order to 0.25–0.35 (24). The moderate correlations may suggest that dietary assessment of acrylamide by FFQ does not fully capture intake or may reflect considerable variation in metabolism of acrylamide from foods across the population. However, it is not clear how nondifferential misclassification of estimated acrylamide intake would lead to an inverse association among women.
Perhaps we should revisit the commentary by Boffetta et al. (28) published last year in the Journal, which presents an in-depth discussion of false-positive results, their causes, and their consequences. The authors of the commentary raise several important points around sources of false-positive results relevant for the present investigation. For example, there may be a small bias due to confounding by unidentified dietary factors that are linked to the specific foods that contribute to acrylamide in the Dutch diet and which are associated with a reduced risk of lung cancer. We should be cautious, as Hogervorst et al. correctly point out, in interpreting the results of subgroup analyses (eg, stratifying by sex) that are data driven rather than based on a priori hypotheses. Finally, we should not discount the role that chance may be playing in leading to the inverse association among women only. The final message put forth by Boffetta et al. is to err toward "epistemological modesty" in interpreting results of our epidemiological studies. In our view, speculation about the potential mechanisms of the protective effect of acrylamide on lung cancer among women should await confirmation of the association in additional studies. Perhaps the safer conclusion we can make from the Netherlands study is that the findings do not support a positive association between acrylamide intake from diet and risk of lung cancer.
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J Natl Cancer Inst 2009 101: 613.
J Natl Cancer Inst 2009 101: 613.
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